Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the invention relates to a new compound derived from pyridylsulfonylurea, methods for its preparation, and pharmaceutical compositions containing it.
• the present invention relates to the compound of formula (I): which is N - ⁇ [4- (cycloheptylamino) pyrid-3-yl] sulfonyl ⁇ N '- (cycloheptyl) urea, and its addition salts with a pharmaceutically acceptable acid or base.
• the compound of formula (I) is therefore a special case of the compounds of formula (a) where X is an oxygen atom, and where R and R1 each represent a cycloheptyl radical.
• this compound appear to a person skilled in the art, in the light of application EP 445 039, as having a particular interest since although included in the general formula of claim 1, it does not is neither specifically described nor claimed.
• the Applicant has discovered that the compound of the invention has a very powerful and surprising antioedematous activity compared to the closest compound to the prior art.
• the Applicant has also discovered that the compound of the invention associates with its anti-edema activity a potent anti-hypoxic and anti-ischemic activity. This activity was quite unexpected since the prior art, and in particular application EP 445 039, does not mention or suggest such an activity.
• the toxicity of the compound of the invention was also evaluated in rats and mice, it turned out that the compound of the invention is particularly well tolerated since at doses greater than 3,200 mg / kg per os, it no mortality was observed.
• the present invention also relates to the process for the preparation of the compound of formula (I) characterized in that: reacting the [4- (cycloheptylamino) pyrid-3-yl] sulfonamide of formula (II): with a compound of formula (III): Hal - CO - O - R1 (III) in which Hal represents a halogen atom and R1 represents an alkyl containing from 1 to 6 carbon atoms, to obtain a compound of formula IV: in which R1 is as defined above, which is then reacted with cycloheptylamine to yield the compound of formula (I) which is, if desired, purified and transformed, if necessary, into its addition salt with a pharmaceutically acceptable acid or base.
• the invention also extends to a second process for the preparation of the compound of formula (I) characterized in that: the [4- (cycloheptylamino) pyrid-3-yl] sulfonamide of formula II is reacted in a polar solvent: with cycloheptyl isocyanate of formula (V) to lead to the compound of formula (I) which is, if desired, purified and transformed, if necessary, into its addition salt with a pharmaceutically acceptable acid or base.
• the Applicant has discovered that the compound of the invention has a very interesting and surprising pharmacological activity in view of the closest compound to the prior art.
• the compound of the invention has a very powerful antioedematous activity (Example 3 of the present application: Study of the antioedematous activity in rabbits), and surprising compared to the compound of Example 8 of EP 445 039 (N - ⁇ [4- (cyclooctylamino) pyrid-3-yl] sulfonyl ⁇ N '- (cycloheptyl) urea) which is the structurally closest compound of the prior art.
• the compound of this example 8 differs in fact only by the presence of an additional carbon chain in the cycloalkyl group in position 4 of the pyridic nucleus.
• the inhibitory activity of the compound of the invention on the Cl ⁇ channel is also much higher than that of the compound of Example 8 EP 445 039 (N - ⁇ [4- (cyclooctylamino) pyrid-3-yl] sulfonyl ⁇ N '- (cycloheptyl) urea), which is the structurally closest compound of the prior art and which is also the compound appearing the most active in the inhibition of the Cl ⁇ channel (example 19 of application EP 445 039).
• the Applicant has discovered that the compound of the invention also possessed a remarkable and very potent anti-ischemic and anti-hypoxic activity.
• the compound of the invention indeed makes it possible to obtain, both in vitro and in vivo, an astonishing protection against hypoxia (hypoxia test on cultured astrocytes and normobaric hypoxia test on mice, described in our pharmacological study: examples 5 and 6 of the present application) and against ischemia (test of ischemia caused in gerbils: example 7 of the present application).
• the remarkable pharmacological properties of the compound of the present invention make it particularly valuable in the prevention and treatment of ischemic and hypoxic disorders and of peripheral and central edemas.
• the compounds of the invention are therefore useful in the treatment and prevention of cerebral ischemia, cerebrovascular hypoxia, cerebrovascular anoxia, head trauma, encephalopathies, neuro-vegetative diseases, convulsions post-ischemic, and senescent disorders, as well as for the treatment and prevention of peripheral ischemia, and in cardiology of myocardial ischemia and coronary ischemia as well as their different clinical expressions: angina chest, myocardial infarction, arrhythmia, vascular spasm, heart failure, as well as in ophthalmology and otolaryngology in chorio-retinal vascular attacks, vertigo of vascular origin, vertigo of Meniere or tinnitus.
• the invention also extends to pharmaceutical compositions containing as active ingredient the compound of formula (I) or one of its addition salts, with a pharmaceutically acceptable acid or base, in combination with one or more pharmaceutically acceptable excipients
• compositions according to the invention there may be mentioned, by way of example and without limitation, those which are suitable for oral, parenteral, ocular, per or trans-cutaneous, nasal, rectal, perlingual or respiratory administration. , and in particular the injections, aerosols, eye or nose drops, tablets, sublingual tablets, capsules, capsules, tablets, lollipops, suppositories, creams, ointments, gels.
• the preparations thus obtained are generally in dosage form and may contain, depending on the conditions treated, the age and sex of the patient, from 0.01 to 100 mg of active principle (preferably from 0.01 to 10 mg, for example from 0.01 to 0.1 mg) one to three times a day.
• reaction mixture is filtered and the filtrate is evaporated under vacuum.
• residue is then dissolved in a water / acetone mixture (90/10) containing NaHCO3.
• Stage B N - ⁇ [4- (cycloheptylamino) pyrid-3-yl] sulfonyl ⁇ N '- (cycloheptyl) urea
• 3 g of the compound obtained in Stage A are dissolved in 40 cm3 of anhydrous toluene and 2 cm3 of cycloheptylamine. 3 g of molecular sieve (0.4 nm) are also added.
• the solution is brought to reflux and the progress of the reaction is monitored by thin layer chromatography.
• the excess amine is extracted into the alkaline solution with ether, then the aqueous phase is clarified with charcoal, filtered, and brought to a pH of 6.5 with hydrochloric acid.
• N - ⁇ [4- (cycloheptylamino) pyrid-3-yl] sulfonyl ⁇ N '- (cycloheptyl) urea thus obtained can be optionally recrystallized from a hydroalcoholic solution. Yield: 68% Melting point: 172-174 ° C
• the edema is caused in vivo by subjecting the animals to hypoxic episodes of 30 min by bilateral occlusion of the common carotid arteries.
• the comparative analysis is then carried out at the frontal lobes between the control animals and the animals treated with the test compounds.
• the experiments are carried out on adult rabbits (Fauves de Bourgogne, 2 - 2.5 kg). Seven animals are used per experimental situation. Astrocytic swelling is induced by subjecting the animals' brains to hypoxic episodes of 30 min by bilateral occlusion of the common carotid arteries. Ultrastructural studies are carried out on samples taken from the frontal lobes of control, hypoxic, and treated-hypoxic rabbits.
• the animals preanesthetized with chlorpromazine (65 mg / kg) and anesthetized with sodium pentobarbital (20 mg / kg) receive the test substance, by injection into the marginal ear vein, 10 min before the start of hypoxia .
• the initial dose of the test substance is 10 mg / kg.
• the animals are sacrificed by intracardiac perfusion of the fixing solution (glutaraldehyde at 2.5% in 0.1 M phosphate buffer, pH 7.4).
• the samples taken continue their fixation in the same fixative for 1 hour, are washed in 0.1 M phosphate buffer supplemented with 0.18 M sucrose, treated with 1% osmium tetroxide in phosphate buffer, then dehydrated, included and cut on an ultratome using a diamond knife; after which the sections, mounted on grids, are observed on an electron microscope.
• the compound of the invention appears to have a powerful antioedematous activity since the brain sections from animals pretreated with 10 mg / kg of the compound of the invention do not reveal any edema.
• the compound of the invention has been compared to Torasemide which is one of the most powerful diuretics known currently acting at the level of the ascending branch of the loop of Henlé.
• Astrocytes in culture constitute a model of choice for the search for cytoprotective activity in the face of a situation of hypoxia.
• the first visible cellular reaction to any brain attack is an attack on astrocytic integrity, even though the neurons, oligodendrocytes, and endothelial cells still have a normal morphological profile.
• the astrocyte has a major role in the brain, particularly in the development of neurotransmitter amino acids and in the preservation of extracellular ion balance.
• the Applicant has therefore tested the effect of the compounds of the invention on the cell protection of cultured astrocytes placed in hypoxia situation by analyzing an enzymatic marker (lactate dehydrogenase or LDH) which makes it possible to measure the cell lysis of astrocytes .
• an enzymatic marker lactate dehydrogenase or LDH
• Astrocytes from primary culture rats are prepared from cortices from the brains of newborn rats.
• the hypoxic treatment consists in exposing the cells, in a humid atmosphere, to a gas mixture consisting of 95% N2 and 5% CO2, at 37 ° C for 15 hours.
• test compounds are added to the culture medium 12 hours before hypoxia. A second addition is made at the end of the hypoxic period. Two hours after the end of hypoxia, the lactate dehydrogenase extracellular activity is measured by spectrophotometric assay at 340 nm on the culture medium.
• the compound of the invention has exceptional anti-hypoxic activity since it makes it possible to avoid cell lysis, normally caused by hypoxia and measured in the control experiment without product.
• the comparison between the compound of the invention and furosemide after a period of 18 h of hypoxia shows that, at a concentration of 10 ⁇ M, the compound of the invention allows protection astrocyte close to 90% while furosemide, at this same concentration, has no protective activity.
• Animals (mice) are placed in an oxygen-poor atmosphere, which causes the onset of suffocation.
• mice Male mice (Swiss CD1) weighing 25-30 g are kept for 1 week before any experiment in the usual conditions of animal house (20-22 ° C, 55% humidity, light / dark cycle 12/12, industrial food and unlimited water).
• mice are placed in a box (7 ⁇ 5 ⁇ 5 cm) in which an atmosphere poor in oxygen is created by the passage of an air at 96% N2 and 4% O2.
• mice receive a dose of the test compounds intraperitoneally.
• the compound of the invention exhibits significant anti-hypoxic activity from the dose of 0.1 mg / kg whereas the compound closest to the prior art (Example 8 of application EP 445 039, N- ⁇ [4- (cyclooctylamino) pyrid-3-yl] sulfonamide ⁇ N '- (cycloheptyl) urea has no antihypoxic activity even at a dose of 20 mg / kg, that is to say a dose 200 times higher.
• the occlusion of a carotid in the gerbil makes it possible to reproduce, unlike other animal species, the pathology of human ischemia.
• the Applicant has therefore tested the influence of the compound of the invention on the survival of gerbils having undergone cerebral ischemia by ligation of the left carotid artery.
• the gerbils "sensitive" to Ketalar® are anesthetized at a dose of 60 mg / kg intraperitoneally and 30 minutes before ligation of the left carotid artery, different concentrations of the compound of the invention are administered orally in the presence of 10% gum arabic and in a volume of 0.1 cm3.
• the compound of the invention has a very important anti-ischemic protective activity.
• the compound of the invention administered per os, from the dose of 0.1 mg / kg, makes it possible to obtain a high percentage survival (83% at 0.1 mg / kg, activity much higher than that of the closest compound to the prior art (Example 8 of application EP 445 039)).
• the study of the treated animals shows that the compound of the invention allows, up to 96 h, significant behavioral protection.
• the compound of the invention has in particular a strong inhibitory activity of post-ischemic convulsions.

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• General Chemical & Material Sciences (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Animal Behavior & Ethology (AREA)
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• Urology & Nephrology (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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• 1992
  • 1992-01-06 FR FR9200031A patent/FR2685917A1/fr active Granted
• 1993
  • 1993-01-05 EP EP93400003A patent/EP0551219A1/de not_active Ceased
  • 1993-01-05 US US08/000,474 patent/US5391559A/en not_active Expired - Fee Related
  • 1993-01-05 AU AU31015/93A patent/AU654607B2/en not_active Ceased
  • 1993-01-05 CA CA002086698A patent/CA2086698A1/fr not_active Abandoned
  • 1993-01-06 NZ NZ245619A patent/NZ245619A/en unknown
  • 1993-01-06 ZA ZA9364A patent/ZA9364B/xx unknown
  • 1993-01-06 JP JP5000691A patent/JPH0684353B2/ja not_active Expired - Lifetime

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